A Randomized, Double-blind, Placebo-controlled, Multicenter, Two-part, Dose Ranging and Confirmatory Study With an Operationally Seamless Design, Evaluating Efficacy and Safety of SAR153191 on Top of Methotrexate (MTX) in Patients With Active Rheumatoid Arthritis Who Are Inadequate Responders to MTX Therapy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Sanofi
- 入组人数
- 1,675
- 试验地点
- 262
- 主要终点
- Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12
研究概览
简要总结
Primary Objectives:
Part A (dose ranging study):
To demonstrate that sarilumab (SAR153191/REGN88) on top of MTX was effective on reduction of signs and symptoms of rheumatoid arthritis at 12 weeks.
Part B (pivotal study):
To demonstrate that sarilumab added to MTX was effective in:
- reduction of signs and symptoms of rheumatoid arthritis at 24 weeks
- inhibition of progression of structural damage at 52 weeks
- improvement in physical function at 16 weeks
Secondary Objectives:
Part B:
To demonstrate that sarilumab added to MTX was effective in induction of a major clinical response at 52 weeks
To assess the safety of sarilumab added to MTX
To document the pharmacokinetic profile of sarilumab added to MTX in participants with active rheumatoid arthritis who were inadequate responders to MTX therapy.
详细描述
The total study duration for a participant was 16-22 weeks (Part A) and 56-62 weeks (Part B) broken down as follows:
- Screening: Up to 4 weeks
- Treatment: 12 weeks (Part A) and 52 weeks (Part B)*
- Follow-up: 6 weeks (for participants who would not continue in the long-term extension study).
'*' Participants successfully completing their treatment period would be offered the opportunity to enter the long term extension study LTS11210 (SARIL-RA-EXTEND) (NCT01146652).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Part A: SAR 100 mg qw
Sarilumab 100 mg subcutaneous (SC) injection weekly (qw) on top of MTX for 12 weeks.
干预措施: Sarilumab (Drug)
Part A: SAR 100 mg qw
Sarilumab 100 mg subcutaneous (SC) injection weekly (qw) on top of MTX for 12 weeks.
干预措施: Methotrexate (Drug)
Part A: SAR 100 mg qw
Sarilumab 100 mg subcutaneous (SC) injection weekly (qw) on top of MTX for 12 weeks.
干预措施: Folic Acid (Drug)
Part A: SAR 150 mg qw
Sarilumab 150 mg SC injection qw on top of MTX for 12 weeks.
干预措施: Sarilumab (Drug)
Part A: SAR 150 mg qw
Sarilumab 150 mg SC injection qw on top of MTX for 12 weeks.
干预措施: Methotrexate (Drug)
Part A: SAR 150 mg qw
Sarilumab 150 mg SC injection qw on top of MTX for 12 weeks.
干预措施: Folic Acid (Drug)
Part A: SAR 100 mg q2w
Sarilumab 100 mg SC injection every other week (q2w) alternating with placebo on top of MTX for 12 weeks.
干预措施: Sarilumab (Drug)
Part A: SAR 100 mg q2w
Sarilumab 100 mg SC injection every other week (q2w) alternating with placebo on top of MTX for 12 weeks.
干预措施: Placebo (for sarilumab) (Drug)
Part A: SAR 100 mg q2w
Sarilumab 100 mg SC injection every other week (q2w) alternating with placebo on top of MTX for 12 weeks.
干预措施: Methotrexate (Drug)
Part A: SAR 100 mg q2w
Sarilumab 100 mg SC injection every other week (q2w) alternating with placebo on top of MTX for 12 weeks.
干预措施: Folic Acid (Drug)
Part A: SAR 150 mg q2w
Sarilumab 150 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks.
干预措施: Sarilumab (Drug)
Part A: SAR 150 mg q2w
Sarilumab 150 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks.
干预措施: Placebo (for sarilumab) (Drug)
Part A: SAR 150 mg q2w
Sarilumab 150 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks.
干预措施: Methotrexate (Drug)
Part A: SAR 150 mg q2w
Sarilumab 150 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks.
干预措施: Folic Acid (Drug)
Part A: SAR 200 mg q2w
Sarilumab 200 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks.
干预措施: Sarilumab (Drug)
Part A: SAR 200 mg q2w
Sarilumab 200 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks.
干预措施: Placebo (for sarilumab) (Drug)
Part A: SAR 200 mg q2w
Sarilumab 200 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks.
干预措施: Methotrexate (Drug)
Part A: SAR 200 mg q2w
Sarilumab 200 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks.
干预措施: Folic Acid (Drug)
Part A: Placebo qw
Placebo (for sarilumab) qw on top of MTX for 12 weeks.
干预措施: Placebo (for sarilumab) (Drug)
Part A: Placebo qw
Placebo (for sarilumab) qw on top of MTX for 12 weeks.
干预措施: Methotrexate (Drug)
Part A: Placebo qw
Placebo (for sarilumab) qw on top of MTX for 12 weeks.
干预措施: Folic Acid (Drug)
Part B Cohort 1: Non-selected Doses
Sarilumab 100 mg qw, 150 mg qw or 100 mg q2w SC injections as in Part A on top of MTX up to dose selection. After dose selection, participants were not continued but were allowed to participate in the open-label, long-term, extension study SARIL-RA-EXTEND (LTS11210).
干预措施: Sarilumab (Drug)
Part B Cohort 1: Non-selected Doses
Sarilumab 100 mg qw, 150 mg qw or 100 mg q2w SC injections as in Part A on top of MTX up to dose selection. After dose selection, participants were not continued but were allowed to participate in the open-label, long-term, extension study SARIL-RA-EXTEND (LTS11210).
干预措施: Placebo (for sarilumab) (Drug)
Part B Cohort 1: Non-selected Doses
Sarilumab 100 mg qw, 150 mg qw or 100 mg q2w SC injections as in Part A on top of MTX up to dose selection. After dose selection, participants were not continued but were allowed to participate in the open-label, long-term, extension study SARIL-RA-EXTEND (LTS11210).
干预措施: Methotrexate (Drug)
Part B Cohort 1: Non-selected Doses
Sarilumab 100 mg qw, 150 mg qw or 100 mg q2w SC injections as in Part A on top of MTX up to dose selection. After dose selection, participants were not continued but were allowed to participate in the open-label, long-term, extension study SARIL-RA-EXTEND (LTS11210).
干预措施: Folic Acid (Drug)
Part B: SAR 150 mg q2w (Cohort 1[Selected Dose]+Cohort 2)
Sarilumab 150 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.
干预措施: Sarilumab (Drug)
Part B: SAR 150 mg q2w (Cohort 1[Selected Dose]+Cohort 2)
Sarilumab 150 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.
干预措施: Methotrexate (Drug)
Part B: SAR 150 mg q2w (Cohort 1[Selected Dose]+Cohort 2)
Sarilumab 150 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.
干预措施: Folic Acid (Drug)
Part B: SAR 200 mg q2w (Cohort 1[Selected Dose]+Cohort 2)
Sarilumab 200 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.
干预措施: Sarilumab (Drug)
Part B: SAR 200 mg q2w (Cohort 1[Selected Dose]+Cohort 2)
Sarilumab 200 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.
干预措施: Methotrexate (Drug)
Part B: SAR 200 mg q2w (Cohort 1[Selected Dose]+Cohort 2)
Sarilumab 200 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.
干预措施: Folic Acid (Drug)
Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2)
Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.
干预措施: Placebo (for sarilumab) (Drug)
Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2)
Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.
干预措施: Methotrexate (Drug)
Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2)
Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab.
干预措施: Folic Acid (Drug)
结局指标
主要结局
Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12
时间窗: Baseline to Week 12
ACR20 response was defined, based on guidelines set forth by the American College of Rheumatology (ACR), as ≥20 % improvement in tender joint count and swollen joint count as well as ≥20% improvement in at least 3 of 5 following measures: C-Reactive Protein (CRP), Participant assessment of pain; Participant's global assessment of disease activity; Physician global assessment of disease activity; and Health Assessment Question-Disability Index (HAQ-DI). Missing data imputed by Last Observation Carried Forward (LOCF).
Part B: Percentage of Participants Achieving ACR20 Response at Week 24
时间窗: Baseline to Week 24
ACR20 improvement responses were determined without imputation of missing post-baseline values. In addition data collected after treatment discontinuation or rescue was set to missing. Responder status was determined if possible. With these rules, participants automatically became non-responders for all time points beyond the time point they started rescue treatment or discontinued study treatment.
Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16
时间窗: Baseline, Week 16
HAQ-DI was a participant-reported questionnaire that assesses the difficulty of performing daily activities: dress/groom, arise, eat, walk, reach, grip, hygiene and common activities. Overall score range from 0=least difficulty to 3=extreme difficulty. An increase in the score indicates a worsening of physical function while a decrease in the score represents improvement. Data collected after treatment discontinuation was set to missing.
Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52
时间窗: Baseline, Week 52
The Sharp method modified by D. van der Heijde involves separate scores for erosions and joint space narrowing based on radiographs to assess the degree of structural damage. Total score range from 0 (normal) to 448 (worst possible total score). An increase in total score represents progression of structural damage. Missing data were imputed by the linear extrapolation method.
次要结局
- Part B: Percentage of Participants Achieving a Major Clinical Response at Week 52(Baseline up to Week 52)